Analgesic 4-hydroxy-3-quinolinecarboxamides

ABSTRACT

Novel compounds of the formula ##STR1## wherein X is in the 5,6,7 or 8 position and is selected from the group consisting of hydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 4 carbon atoms, CF 3  O--, CF 3  S-- and CF 3  --, R 1  &#39; is selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, R 2  &#39; is selected from the group consisting of hydrogen or an optionally unsaturated ring able to contain one or more heteroatoms of the group consisting of --S--, --O-- and --N-- optionally substituted with one or more members of the group consisting of (a) halogens, (b) alkyl of 1 to 4 carbon atoms optionally substituted with NH 2 , --NHAlK or --N---(AlK) 2  and AlK is alkyl of 1 to 3 carbon atoms, (c) phenyl, (d) alkoxy of 1 to 4 carbon atoms, (e) --OH, (f) --CF 3  and (g) --NO 2  or R 1  &#39; together with the nitrogen atom to which they are attached form an optionally unsaturated ring, the said ring then being connected to the nitrogen atom by a double bond, R 3  is selected from the group consisting of hydrogen, halogen and alkyl of 1 to 4 carbon atoms, R 4  is selected from the group consisting of hydrogen and halogen, R 5  is a halogen with the proviso that R 3 , R 4  and R 5  can not all be fluorine and R 6  is selected from the group consisting of hydrogen, alkyl of 1 to 8 carbon atoms and an acyl of an organic carboxylic acid of 2 to 8 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts and their salts with non-toxic, pharmaceutically acceptable bases having a remarkable analgesic activity, a very weak anti-inflammatory activity and a good tolerance by the gastrointestinal system and their preparation and their intermediates.

STATE OF THE ART

U.S. Pat. Nos. 3,992,540 and No. 4,107,310 and copending, commonlyassigned U.S. patent application Ser. No. 97,711 filed Nov. 27, 1979,now U.S. Pat. No. 4,299,831, describe 3-quinoline-carboxamides whichdiffer from the compounds of the invention by their substitution in the2-position. The compounds of U.S. Pat. No. 3,992,540 are unsubstitutedin the 2-position while the compounds of U.S. Pat. No. 4,107,310 aresubstituted in the 2-position with an alkyl group. The compounds ofapplication Ser. No. 97,711 are substituted in the 2-position with a--CF₃ group.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I' and their salts with acids and bases and a novel process fortheir preparation and novel intermediates therefor.

It is another object of the invention to provide novel analgesiccompositions and to a novel method of relieving pain in warm-bloodedanimals.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel 4-hydroxy-3-quinoline-carboxamides of the invention areselected from the group consisting of compounds of the formula ##STR2##wherein X is in the 5,6,7 or 8 position and is selected from the groupconsisting of hydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of1 to 4 carbon atoms, CF₃ O--, CF₃ S-- and CF₃ --, R₁ ' is selected fromthe group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, R₂ 'is selected from the group consisting of hydrogen or an optionallyunsaturated ring able to contain one or more heteroatoms of the groupconsisting of --S--, --O-- and --N-- optionally substituted with one ormore members of the group consisting of (a) halogens, (b) alkyl of 1 to4 carbon atoms optionally substituted with NH₂, --NHAlK or --N--(AlK)₂and AlK is alkyl of 1 to 3 carbon atoms, (c) phenyl, (d) alkoxy of 1 to4 carbon atoms, (e) --OH, (f) --CF₃ and (g) --NO₂ or R₁ ' and R₂ 'together with the nitrogen atom to which they are attached form anoptionally unsaturated ring, the said ring then being connected to thenitrogen atom by a double bond, R₃ is selected from the group consistingof hydrogen, halogen and alkyl of 1 to 4 carbon atoms, R₄ is selectedfrom the group consisting of hydrogen and halogen, R₅ is a halogen withthe proviso that R₃, R₄ and R₅ can not all be fluorine and R₆ isselected from the group consisting of hydrogen, alkyl of 1 to 8 carbonatoms and an acyl of an organic carboxylic acid of 2 to 8 carbon atomsand their non-toxic, pharmaceutically acceptable acid addition salts andtheir salts with non-toxic, pharmaceutically acceptable bases.

When R₁ ' is alkyl, it is preferably methyl or ethyl and when X is anhalogen, it is preferably chlorine although it may be fluorine, bromineor iodine. When X is alkyl, it is preferably methyl, ethyl, n-propyl,n-butyl, n-pentyl, isopropyl or isobutyl. When X is alkoxy, it ispreferably methoxy, ethoxy or n-propoxy.

When R₂ ' is a ring, it is preferably thiazolyl, phenyl, pyridinyl,thienyl, benzothiazolyl, oxazolyl or imidazolyl. When R₂ ' is asubstituted ring, the substituents are preferably selected from thegroup consisting of chlorine, methyl, ethyl, dimethylaminomethyl,phenyl, methoxy, ethoxy, --OH, --CF₃ and --NO₂.

When R₃ is alkyl, it is preferably methyl or ethyl and when R₃ ishalogen, it is preferably fluorine, chlorine or bromine. R₄ ispreferably fluorine, chlorine or bromine and R₅ is preferably chlorineor bromine. When R₆ is alkyl, it is preferably methyl or ethyl and whenR₆ is acyl, it is preferably derived from an aliphatic carboxylic acidsuch as acetic acid, propionic acid or butynyl carboxylic acid.

Example of suitable acids to form the non-toxic, pharmaceuticallyacceptable acid addition salts are mineral acids such as hydrochloricacid, hydrobromic acid, sulfuric acid and phosphoric acid and organicacids such as acetic acid, citric acid, oxalic acid, formic acid,alkylsulfonic acids such as methanesulfonic acid or ethanesulfonic acidor arylsulfonic acids such as p-toluenesulfonic acid or benzenesulfonicacid.

Examples of suitable non-toxic, pharmaceutically acceptable salts formedwith bases are alkali metal salts such as sodium and potassium andamines such as trimethylamine and dimethylamine.

Among the preferred compounds of the invention are those of the formula##STR3## wherein X, R₃, R₄ and R₅ have the above definition, R₁ isselected from the group consisting of hydrogen and alkyl of 1 to 4carbon atoms, R₂ is selected from the group consisting of thiazolyl,4,5-dihydrothiazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl,pyrimidyl and tetrazolyl all optionally substituted with alkyl of 1 to 4carbon atoms and phenyl optionally substituted with at least one memberof the group consisting of --OH, alkyl of 1 to 4 carbon atoms, alkoxy of1 to 4 carbon atoms, halogen, --CF₃ and --NO₂ and their non-toxic,pharmaceutically acceptable salts of acids and bases.

Particularly preferred compounds of formula I are those wherein R₃ ishydrogen, alkyl or the same halogen as R₅, those wherein R₄ is hydrogenor the same halogen as R₅, those wherein X is --CF₃, those wherein R₁ ishydrogen, those wherein R₃ and R₄ are individually hydrogen or chlorineand R₅ is chlorine and those wherein ##STR4## is --CHCl₂ and theirnon-toxic, pharmaceutically acceptable salts with acids or bases.

Preferably R₂ is thiazolyl and the most preferred compound of formula I'is2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamideand its non-toxic, pharmaceutically acceptable salts with acids andbases.

The novel process of the invention for the preparation of the compoundsof formula I' comprises reacting a compound of the formula ##STR5##wherein X has the above definition, AlK' is alkyl of 1 to 8 carbon atomsand R is selected from the group consisting of hydrogen and alkyl of 1to 4 carbon atoms with a halogenation agent and then with a halogenationagent different from the first to obtain a compound of the formula##STR6## wherein R₃ ', R₄ ' and R₅ ' have the same definition of as R₃,R₄ and R₅, respectively, and, if desired, reacting the compound offormula III_(A) with a compound of formula Hal₁ --M wherein Hal₁ is ahalogen and M is an alkali metal to obtain a compound of the formula##STR7## wherein R₃ " is selected from the group consisting of hydrogen,Hal₁ and alkyl of 1 to 4 carbon atoms, R₄ " is selected from the groupconsisting of hydrogen and Hal₁ and R₅ is Hal₁, reacting either compoundIII_(A) or III_(B) with a saponification agent to obtain a compound ofthe formula ##STR8## optionally transforming the said acid into afunctional derivative thereof, reacting the acid of formula IV or itsfunctional derivative with a compound of the formula ##STR9## wherein R₁' and R₂ ' have the above definitions to obtain a compound of theformula ##STR10## which is a compound of formula I' wherein R₆ ishydrogen and optionally reacting the latter with an etherification agentor esterification agent to obtain a compound of the formula ##STR11##wherein R₆ ' is selected from the group consisting of alkyl of 1 to 8carbon atoms and acyl of an organic carboxylic acid of 2 to 8 carbonatoms which is a compound of formula I' wherein R₆ is other thanhydrogen and optionally reacting the compounds of formula I_(A) ' orI_(B) ' with a non-toxic, pharmaceutically acceptable acid or base toform the corresponding salt.

A preferred mode of the said process comprises reacting a compound ofthe formula ##STR12## wherein X and AlK' have the above definitions witha halogenation agent to obtain a compound of the formula ##STR13##wherein R₃ ''' and R₄ are selected from the group consisting of hydrogenand the same halogen as R₅, reacting the latter with a saponificationagent to obtain a compound of the formula ##STR14## optionallytransforming the said acid into a functional derivative thereof,reacting the acid of formula IV_(a) or its functional derivative with acompound of formula V to obtain a compound of the formula ##STR15##which is a compound of formula I' wherein R₆ is hydrogen and R₃ has thevalues of R₃ ''', optionally reacting the latter with an etherificationagent or an esterification agent to obtain a compound of the formula##STR16## which is a compound of formula I' wherein R₆ is other thanhydrogen and R₃ is R₃ ''' and optionally reacting a compound of formulaI_(C) ' or I_(D) ' with a non-toxic, pharmaceutically acceptable acid orbase to form the corresponding salt.

Examples of suitable halogenation agents are the halogens, cuprichalides and N-bromo or N-chloro-amides such as N-bromo-succinimide,N-chloro-succinimide, N-bromo-acetamide and N-chloro-acetamide. Toobtain mono, di- or tri-halo compounds, different quantities of thehalogenation agents are used.

Examples of functional acid derivatives are the acid chloride, loweralkyl esters, its anhydride and mixed anhydrides. The condensation ofthe acid or its functional derivative with the amine of formula V iseffected in an inert organic solvent such as benzene, toluene, pyridineor ethyl acetate in the presence of a basic agent such as triethylamine.The etherification or esterification of the compounds of formulae I_(A)' and I_(C) ' may be effected by known methods.

In a preferred mode of the said process of the invention, AlK' is methylor ethyl and the halogenation agent is a N-haloamide such asN-chloro-acetamide, N-bromo-acetamide, N-chloro-succinimide orN-bromo-succinimide with the reaction being effected in a solvent suchas carbon tetrachloride, chloroform or acetic acid in the presence of aradical initiator such as light, azobisisobutyronitrile or a peroxidesuch as benzoyl peroxide. Hal₁ is preferably fluorine and M ispreferably potassium. The saponification agent is sodium hydroxide orpotassium hydroxide. The most preferred halogenation agents areN-bromo-succinimide or N-chloro-succinimide.

In a modification of the process of the invention, a compound offormulae III_(A), III_(B) or III_(a) is reacted with a compound offormula V in the presence of a trialkylaluminum to obtain a compound offormula I_(A) ' or I_(C) ' which can then be reacted further. Thetrialkylaluminum is preferably trimethylaluminum or triisobutylaluminum.

Another process of the invention for the preparation of a compound offormula I' comprises reacting a compound of the formula ##STR17##wherein X has the above definition with an acid of the formula ##STR18##wherein R₃, R₄ and R₅ have the above definition or a functionalderivative thereof to obtain a compound of the formula ##STR19##reacting the latter with a compound of the formula ##STR20## wherein R₁' and R₂ ' have the above definition to obtain a compound of the formula##STR21## cyclizing the latter in the presence of an alkaline agent toobtain a compound of formula I_(A) ' which can be reacted with anetherification agent or esterification agent to form the compound offormula I_(B) ' and optionally reacting the compound of formula I_(A) 'or I_(B) ' with a non-toxic, pharmaceutically acceptable acid or base toform the corresponding salt.

In a preferred embodiment of the said process, the functional derivativeof the acid of formula VII is the acid halide or anhydride. The reactionof the compounds of formulae VIII and IX is preferably effected in thepresence of an organolithium such as butyllithium or a lithium amidesuch as lithiumdiisopropylamide. The cyclization of the compound offormula X is effected in the presence of an alkali metal hydride such assodium hydride, an alkali metal carbonate such as sodium carbonate orpotassium carbonate or an amine such as piperidine, 4-amino-pyridine,triethylamine, 1,5-diazabicyclo[4,3,0]-non-5-ene,1,4-diazabicyclo[2,2,2]octane or 1,5-diazabicyclo[5,4,0]undec-5-ene.

The starting materials of formulae II and VI are generally knownproducts and may be prepared by the processes described in French Pat.No. 2,340,735 and No. 2,157,874.

The novel intermediate compounds of the invention are the compounds offormulae III_(A), III_(B), IV, VIII and X and especially those offormulae III_(a) and IV_(a).

The novel analgesic compositions of the invention are comprised of ananalgesically effective amount of at least one compound of formula I'and their non-toxic, pharmaceutically acceptable salts with acids andbases and a pharmaceutical carrier or excipient. The compositions may bein the form of tablets, dragees, gelules, granules, suppositories,injectable solutions or suspensions, pomades, cremes, gels or aerosolpreparations.

Examples of suitable excipients are talc, arabic gum, lactose, starch,magnesium stearate, cacao butter, aqueous or non-aqueous vehicles, fattybodies of animal or vegetable origin, paraffinic derivatives, glycols,diverse wetting agents, emulsifiers or dispersants and preservatives.

The said compositions have an excellent analgesic activity, a very weakanti-inflammatory activity and are well tolerated in thegastrointestinal tract. The compositions therefore are useful fortreatment of muscular, articular or nervous pain, dental pain, migrainesas well as for rheumatic affections.

The novel method of the invention for relieving pain in warm-bloodedanimals, including humans, comprises administering to warm-bloodedanimals an analgesically effective amount of at least one compound offormula I' and their non-toxic, pharmaceutically acceptable salts withacids and bases. The compounds may be administered orally, rectally,parenterally or topically on the skin or mucous. The effective dose willvary depending on the compound, the cause of pain and the method ofadministration but the preferred effective daily oral dose is 0.4 to 40mg/kg.

In the following examples there are described several preferredembodiments to illustrate the invention. However, it should beunderstood that the invention is not intended to be limited to thespecific embodiments.

EXAMPLE 12-(dichloromethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide-PROCEDUREA STEP A: Ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate

A mixture of 11.92 g of ethyl2-methyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate, 400 ml ofcarbon tetrachloride, 13.30 g of N-chloro-succinimide and 600 mg ofbenzoyl peroxide was refluxed for 24 hours and was then cooled to roomtemperature and filtered. The filtrate was evaporated to dryness toobtain 17 g of an oil which was chromatographed over silica gel. Elutionwith methylene chloride yielded 13.6 g of a product melting at 80° to85° C. which was empasted with petroleum ether (b.p.=60°-80° C.) and wasvacuum filtered. The product was rinsed and dried to obtain 8.8 g ofethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylatemelting at 88° C.

STEP B:2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylic acid

A solution of 22 g of the product of Step A, 220 ml of ethanol and 110ml of sodium hydroxide was stirred at room temperature for 36 hours andthe ethanol was then evaporated at less than 40° C. under reducedpressure. The solution was diluted with 200 ml of water and ice and thepH was adjusted to 1 by addition of concentrated hydrochloric acid. Themixture was vacuum filtered and the product was washed with water andthen was dissolved in ether. The solution was filtered and the filtratewas dried and evaporated to dryness under reduced pressure to obtain 18g of 2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylicacid which was used as is for the next step.

STEP C:2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

A solution of 15 g of the product of Step B, 400 ml of anhydrous benzeneand 16 ml of thionyl chloride was refluxed for 90 minutes and then thebenzene and excess thionyl chloride were removed by distillation underreduced pressure to obtain2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxylicacid chloride.

A solution of the said product in 120 ml of ethyl acetate was admixedwith stirring under an inert atmosphere with a solution of 4.41 g of2-amino-thiazole, 50 ml of anhydrous ethyl acetate and 18.5 ml oftriethylamine and the mixture was refluxed for one hour and stoodovernight at room temperature. The mixture was filtered and the filtratewas washed with aqueous sodium chloride to avoid emulsions, dried andevaporated to dryness under reduced pressure. The residue was solidifiedin 150 ml of 20% hydrochloric acid and the mixture was vacuum filtered.The product was washed with water until the wash water was neutral andwas dissolved damp in 50 ml of N sodium hydroxide solution. The solutionwas filtered and the filtrate was acidified to a pH of 4-5 with 50%hydrochloric acid. The mixture was iced and was vacuum filtered. Theproduct was washed with water and dried under reduced pressure at 90° C.to obtain 8.5 g of raw product which was crystallized from ethyl acetateto obtain 5.7 g of2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 204° C.

EXAMPLE 22-dichloromethyl-4-hydroxy-N-phenyl-8-trifluoromethyl-3-quinoline-carboxamide-PROCEDUREB

17.5 ml of a 25% solution of trimethylaluminum in hexane were added at15° to 18° C. to a solution of 3.72 g of aniline in 100 ml of methylenechloride and after stirring the mixture for 15 minutes, 7.56 g of theproduct of Step A of Example 1 were added thereto at the sametemperature. The mixture was refluxed for 22 hours and was then pouredinto 100 ml of an iced 20% aqueous hydrochloric acid solution. Thedecanted aqueous phase was extracted with ethyl acetate and the combinedorganic phases were washed with water, dried and evaporated to dryness.The crystalline residue was empasted with ether, filtered, dried andcrystallized from ethyl acetate to obtain 1.1 g of2-dichloromethyl-4-hydroxy-N-phenyl-8-trifluoromethyl-3-quinoline-carboxamidewhich after crystallization from ethanol melted at 200°-202° C.(decomposition).

Analysis: C₁₈ H₁₁ N₂ O₂ Cl₂ F₃ ; molecular weight=415.217. Calculated:%C 52.07; %H 2.67; %N 6.75; %Cl 17.08; %F 13.73; Found: C 52.0; H 2.6; N6.7; Cl 17.4; F 13.6

EXAMPLE 32-dichloromethyl-4-hydroxy-N-(2-pyridinyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Example 2, 3.76 g of 2-aminopyridine and 7.36 gof the compound of Step A of Example 1 were reacted and the product wascrystallized from ethyl acetate to obtain 2.7 g of2-dichloromethyl-4-hydroxy-N-(2-pyridinyl)-8-trifluoromethyl-3-quinoline-carboxamidewhich after crystallization from methanol melted at 212° C.(decomposition).

Analysis: C₁₇ H₁₀ N₃ Cl₂ F₃ O₂ ; molecular weight=416.199. Calculated:%C 49.06; %H 2.42; %N 10.10; %Cl 17.04; %F 13.69; Found: C 49.0; H 2.3;N 10.0; Cl 17.2; F 13.2

EXAMPLE 42-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

A solution of 30 ml of 25% trimethylaluminum in hexane and 30 ml oftoluene was added at 5° C. to a solution of 13.75 g of 2-amino-thiazolein 150 ml of toluene and after stirring the mixture at 5° to 10° C. for30 minutes, 9.2 g of the product of Step A of Example 1 were addedthereto all at once. After gas evolution ceased, the mixture was heatedat 80° to 85° C. under an inert gas for 31/2 hours. The mixture wasevaporated to dryness under reduced pressure and the residue was addedto 500 ml of N hydrochloric acid. The mixture was stirred for one hourand was filtered. The filter was washed with water, then with a mixtureof water and 2 N sodium hydroxide and finally with water and thecombined alkaline phases were filtered and 2 N hydrochloric acid wasslowly added to the filtrate until the pH was 5. The mixture was vacuumfiltered and the product was washed with water and dried to obtain 7.48g of raw product melting at ≈200° C. The product was crystallized fromethyl acetate with activated carbon treatment to obtain 4.19 g of2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 204° C. which was idential to the product of Example 1.

EXAMPLE 52-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamideSTEP A: Ethyl2-(1-chloroethyl)-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate

A mixture of 9.3 g of ethyl2-ethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate, 200 ml ofcarbon tetrachloride, 4.2 g of N-chlorosuccinimide and 0.45 g ofazobis-isobutyronitrile was stirred at 65° C. maximum for 5 hours undera lamp and was then cooled to 20° C. and was filtered. The filtrate wasevaporated to dryness and the residue was taken up in methylenechloride. The mixture was washed with water, dried and evaporated todryness. The residue was empasted with petroleum ether and dried toobtain 9 g of ethyl2-(1-chloroethyl)-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylatemelting at 104° C.

STEP B:2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Example 4, 1.5 g of 2-aminothiazole and 1.041 gof the product of Step A were reacted and after the addition of Nhydrochloric acid, the mixture was extracted with ethyl acetate. Theorganic phase was washed with water, dried and evaporated to dryness.The residue was chromatographed over silica gel and was eluted withethyl acetate to obtain2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidewhich after crystallization from ether melted at ≈190° C.(decomposition).

EXAMPLE 6

Using the procedure of Example 2, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(4-phenyl-2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 210° C. (decomposition).

EXAMPLE 7

Using the procedure of Example 2, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 240°-250° C. (decomposition).

EXAMPLE 8

Using the procedure of Example 2, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(4,5-dihydroxy-2-thienyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at ≈205° C. (decomposition).

EXAMPLE 9

Using the procedure of Example 2, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(2-benzothiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at ≈265° C. (decomposition).

EXAMPLE 10

Using the procedure of Example 1, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 228°-230° C. (decomposition).

EXAMPLE 11

Using the procedure of Example 1, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(3-methyl-2-thiazolylidene)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 270°-280° C. (decomposition).

EXAMPLE 12

Using the procedure of Example 1, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(5-chloro-2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 245° C. (decomposition).

EXAMPLE 13

Using the procedure of Example 1, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(2-oxazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at ≈220° C. (decomposition).

EXAMPLE 14

Using the procedure of Example 1, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(1-methyl-2-imidazolyl)-8-trifluoromethyl-3-quinolinecarboxamide melting at 240° C. (decomposition).

EXAMPLE 15

Using the procedure of Example 1, ethyl2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate wasreacted to obtain2-dichloromethyl-4-hydroxy-N-(4-dimethylamino-3-methyl-2-thiazolyl)-8-trifluoromethyl-3-quinolinecarboxamide.

EXAMPLE 16

Using the procedure of Step A of Example 5, ethyl2-methyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate waschlorinated to obtain ethyl2-chloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylate whichwas then reacted as in Example 1 to obtain2-chloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 218° C. (decomposition).

EXAMPLE 17

Using the procedure of Step A of Example 5, ethyl2-(1,1-dichloroethyl)-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylatewas prepared and was then further reacted to obtain2-(1,1-dichloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 220° C. (decomposition).

EXAMPLE 182-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamideSTEP A: 2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazin-4-one

A mixture of 17.44 g of 2-amino-3-trifluoromethylbenzoic acid preparedby the process of J. Med. Chem., Vol. 16 (2) (1973), p. 101-106 and34.63 g of dichloroacetyl chloride was progressively heated withstirring and at about 50° C., a hardening of the mass with rapid gasevolution of regular hydrogen chloride occured for one hour. Towards100° C., one observed a fluidization of the reaction mixture, anintensification of hydrogen chloride evolution and an increase in thetemperature of 127° C. The heating was continued until hydrogen chlorideevolution ceased to obtain a brown solution which was cooled in an icebath with stirring. The mixture was vacuum filtered and the product wasempasted with ether, then with methanol and was washed with methanol toobtain 23.82 g of2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at179° C.

STEP B:2-(dichloroacetylamino)-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene-propanamide

87.7 ml of 1.1 mols of n-butyllithium per liter of hexane were addedwith stirring under nitrogen at -3° to -1° C. to a solution of 8.65 g ofN-(2-thiazolyl)-acetamide and 304 ml of tetrahydrofuran and the mixturewas stirred at -3° to -1° C. for 20 minutes and was then cooled to -75°C. A solution of 9.073 g of2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one in 95.5 mlof tetrahydrofuran was added with strong stirring to the mixture at -73°to -75° C. and the mixture was stirred at -75° C. for 2 hours to obtaina brown solution which was poured into a mixture of ice, water andhydrochloric acid. The mixture was vacuum filtered to obtain 935 mg of2-(dichloroacetylamino)-8-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene-propanamidemelting at 223° C.

The aqueous phase was extracted with ethyl acetate and the organic phasewas washed with water, dried and evaporated to dryness. The 15.2 g ofresidue were added to 100 ml of methylene chloride and the mixture wastriturated and was vacuum filtered. The product was empasted with 30 mlof methylene chloride and the mixture was vacuum filtered. The productwas washed with 10 ml of methylene chloride to obtain 7.47 g of thedesired product melting at 223° C.

STEP C:2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

A solution of 8.81 g of the product of Step B in 100 ml ofdimethylformamide was added to a suspension of 1.06 g of sodium hydrideand 50 ml of dimethylformamide and the mixture was stirred at roomtemperature for 4 hours and was poured into an ice-water-hydrochloricacid mixture. The mixture was vacuum filtered and the product was washedwith water and then dissolved in 300 ml of methylene chloride. Thesolution was washed with water, dried over magnesium sulfate and wasfiltered. The filtrate was evaporated to dryness and the 8.5 g ofresidue melting at 175° C. were triturated with ethanol and was vacuumfiltered. The 6.95 g of product were crystallized from 215 ml of ethylacetate to remove insoluble traces to obtain 5.015 g of2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 204° C.

The said process was repeated using potassium carbonate in place ofsodium hydride to obtain the same product melting at 204° C.

EXAMPLE 192-chloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Step A of Example 18,2-amino-3-trifluoromethyl-benzoic acid and chloroacetyl chloride werereacted to obtain2-chloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-3-one melting at76°-78° C. which was then reacted with N-(2-thiazolyl)-acetamide by theprocess of Step B of Example 18 to obtain2-(chloroacetylamino)-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene-propanamidemelting at 192°≈194° C.

The said product was reacted by the procedure of Step C of Example 18with dimethylamino-pyridine in tetrahydrofuran to obtain2-chloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 218° C.

EXAMPLE 202-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Step A of Example 18, 1-chloropropionyl chlorideand 2-amino-3-trifluoromethylbenzoic acid were reacted to obtain2-(1-chloroethyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at112° C. which was reacted by the procedure of Step B of Example 18 withN-(2-thiazolyl)-acetamide to obtain2-(1-chloropropionylamino)-β-oxo-3-trifluoromethyl-N-(2-thiazolyl)-benzene-propanamidemelting at 215° C. The latter was reacted by the procedure of Step C ofExample 18 to obtain2-(1-chloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 190°-192° C.

EXAMPLE 212-(1,1-dichloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Step A of Example 18,2-amino-3-trifluoromethyl-benzoic acid and dichloro-propionyl chloridewere reacted to obtain2-(1,1-dichloroethyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one meltingat 120° C. which was reacted with N-(2-thiazolyl)-acetamide by theprocedure of Step B of Example 18 to obtain2-(1,1-dichloropropionylamino)-β-oxo-N-(2-thiazolyl)-3-trifluoromethyl-benzene-propanamidemelting at 136°-138° C.

The latter product was reacted by the procedure of Step C of Example 18to obtain2-(1,1-dichloroethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 220° C.

EXAMPLE 222-(difluoromethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Step A of Example 18,2-amino-3-trifluoromethyl-benzoic acid and difluoroacetic acid anhydridewere reacted to obtain2-(difluoromethyl)-8-trifluoromethyl-4H-3,1-benzoxazin-4-one melting at82° C. which was reacted with N-(2-thiazolyl)-acetamide by the procedureof Step B of Example 18 to obtain2-(difluoroacetylamino)-β-oxo-3-trifluoromethyl-N-(2-thiazolyl)-benzene-propanamidemelting at 206° C. The latter compound was reacted by the procedure ofStep C of Example 18 to obtain2-(difluoromethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 226° C.

EXAMPLE 232-dichloromethyl-4-hydroxy-N-(2-oxazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Step B of Example 18,2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazin-4-one andN-(2-oxazolyl)-acetamide were reacted to obtain2-(dichloroacetamido)-β-oxo-N-(2-oxazolyl)-3-trifluoromethyl-benzene-propanamidewhich was reacted by the procedure of Step C of Example 18 to obtain2-dichloromethyl-4-hydroxy-N-(2-oxazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at 220°-225° C.

EXAMPLE 242-dichloromethyl-4-hydroxy-N-(1-methyl-2-imidazolyl)-8-trifluoromethyl-3-quinoline-carboxamide

Using the procedure of Step B of Example 18,2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazin-4-one andN-(1-methyl-2-imidazolyl)-acetamide were reacted to obtain2-(dichloroacetamido)-β-oxo-N-(1-methyl-2-imidazolyl)-3-trifluoromethyl-benzene-propanamidewhich was then reacted by the procedure of Step C of Example 18 toobtain2-dichloromethyl-4-hydroxy-N-(1-methyl-2-imidazolyl)-8-trifluoromethyl-3-quinoline-carboxamidemelting at ≈240° C. (decomposition).

EXAMPLE 25

Tablets were prepared containing 50 mg of2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamideand sufficient excipient of lactose, starch, talc and magnesium stearatefor a final tablet weight of 350 mg.

PHARMACOLOGICAL DATA

A. Analgesic Activity

The test used was that of Koster et al [Fed. Proc., Vol. 1B (1959), p.412] in which the intraperitonal injection of acetic acid provokes inmice repeated stretching and twisting movements which persist for morethan 6 hours. Analgesics diminish or prevent this syndrome which isconsidered to be an exteriorization of a diffuse abdominal pain. Asolution of 1% acetic acid in water was used and the dose which gaverise to this syndrome was 0.01 ml/g or 100 mg/k of acetic acid underthese conditions.

The test product was orally administered to the mice which were fastedfor 24 hours before the test 30 minutes before the acetic acid injectionand the stretchings were observed and counted for each mouse for anobservation period of 15 minutes starting immediately after the aceticacid injection. The results expressed as DA₅₀ which is the dose whichdiminished by 50% the number of stretchings as compared to the controlanimals were 0.6 mg/kg for the compound of Example 1.

B. Anti-inflammatory Activity

The anti-inflammatory activity was determined by the planetary edematest provoked by carraghenine in rats. Male rats weighing about 130 to150 g received 0.05 ml of a sterile 1% carraghenine suspension intibio-tarsien joint of a rear foot while simultaneously orallyadministering the compound of Example 1 in a suspension of 0.25% ofcarboxymethylcellulose and 0.02% Tween. The volume of the rear foot wasmeasured before administration and 2, 4, 6, 8 and 24 hours after. Theintensity of the inflammation was maximum 4 to 6 hours after thecarraghenine administration and the difference in volume of the paws ofthe treated and the control animals was evidence of theanti-inflammatory activity of the test compound. The compound of Example1 was inactive at a dose of 50 mg/kg.

Various modifications of the compounds and processes of the inventionmay be made without departing from the spirit or scope thereof and itshould be understood that the invention is intended to be limited onlyas defined in the appended claims.

What we claim is:
 1. A compound selected from the group consisting ofcompounds of the formula ##STR22## wherein X is the 5,6,7 or 8 positionand is selected from the group consisting of hydrogen, halogen, alkyl of1 to 5 carbon atoms, alkoxy of 1 to 4 carbon atoms, CF₃ O--, CF₃ S-- and--CF₃ --, R₁ ' is selected from the group consisting of hydrogen andalkyl of 1 to 4 carbon atoms, R₂ ' is selected from the group consistingof hydrogen, thiazolyl, 4,5-dihydrazolyl, pyridinyl, oxazolyl,isoxazolyl, imidazolyl, pyrimidyl, tetrazolyl, thienyl, benzothiazolyland phenyl, all optionally substituted with one or more members of thegroup consisting of (a) halogens, (b) alkyl of 1 to 4 carbon atomsoptionally substituted with NH₂, --NHAlK or --N--(AlK)₂ and AlK is alkylof 1 to 3 carbon atoms, (c) phenyl, (d) alkoxy of 1 to 4 carbon atoms,(e) --OH, (f) --CF₃ and (g) --NO₂ or R₁ ' and R₂ ' together with thenitrogen atom to which they are attached form thiazolylidene, R₃ isselected from the group consisting of hydrogen, halogen and alkyl of 1to 4 carbon atoms, R₄ is selected from the group consisting of hydrogenand halogen, R₅ is halogen with the proviso that R₃, R₄ and R₅ can notall be fluorine and R₆ is selected from the group consisting ofhydrogen, alkyl of 1 to 8 carbon atoms and an acyl of an organiccarboxylic acid of 2 to 8 carbon atoms and their non-toxic,pharmaceutically acceptable acid addition salts and their salts withnon-toxic, pharmaceutically acceptable bases.
 2. A compound of claim 1wherein R₆ is hydrogen, R₁ ' is selected from the group consisting ofhydrogen and alkyl of 1 to 4 carbon atoms and R₂ ' is selected from thegroup consisting of thiazolyl, 4,5-dihydrothiazolyl, pyridinyl,oxazolyl, isoxazolyl, imidazolyl, pyrimidyl and tetrazolyl alloptionally substituted with alkyl of 1 to 4 carbon atoms and phenyloptionally substituted with at least one member of the group consistingof --OH, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms,halogen, --CF₃ and --NO₂.
 3. A compound of claim 2 wherein R₃ isselected from the group consisting of hydrogen, alkyl of 1 to 4 carbonatoms and the same halogen as R₅ and R₄ is selected from the groupconsisting of hydrogen and the same halogen as R₅.
 4. A compound ofclaim 2 wherein X is --CF₃.
 5. A compound of claim 2 wherein R₁ ishydrogen.
 6. A compound of claim 2 wherein R₅ is chlorine and R₃ and R₄are individually selected from the group consisting of hydrogen andchlorine.
 7. A compound of claim 6 wherein ##STR23## is --CHCl₂.
 8. Acompound of claim 2 wherein R₂ is thiazolyl.
 9. A compound of claim 1which is2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinolinecarboxamideand its salts with non-toxic, pharmaceutically acceptable acids andbases.
 10. An analgesic composition comprising an analgesicallyeffective amount of at least one compound of claim 1 and apharmaceutical carrier.
 11. A composition of claim 10 wherein R₆ ishydrogen, R₁ ' is selected from the group consisting of hydrogen andalkyl of 1 to 4 carbon atoms and R₂ ' is selected from the groupconsisting of thiazolyl, 4,5-dihydrothiazolyl, pyridinyl, oxazolyl,isoxazolyl, imidazolyl, pyrimidyl and tetrazolyl all optionallysubstituted with alkyl of 1 to 4 carbon atoms and phenyl optionallysubstituted with at least one member of the group consisting of --OH,alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen,--CF₃ and --NO₂.
 12. A composition of claim 10 wherein R₃ is selectedfrom the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms andthe same halogen as R₅ and R₄ is selected from the group consisting ofhydrogen and the same halogen as R₅.
 13. A composition of claim 10wherein X is --CF₃.
 14. A composition of claim 10 wherein R₁ ishydrogen.
 15. A composition of claim 10 wherein R₅ is chlorine and R₃and R₄ are individually selected from the group consisting of hydrogenand chlorine.
 16. A composition of claim 10 wherein ##STR24## is--CHCl₂.
 17. A composition of claim 10 wherein R₂ is thiazolyl.
 18. Acomposition of claim 10 wherein the compound is2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamideand its salts with non-toxic, pharmaceutically acceptable acids andbases.
 19. A method of relieving pain in warm-blooded animals comprisingadministering to warm-blooded animals an analgesically effective amountof at least one compound of claim
 1. 20. A method of claim 19 wherein R₆is hydrogen, R₁ ' is selected from the group consisting of hydrogen andalkyl of 1 to 4 carbon atoms and R₂ ' is selected from the groupconsisting of thiazolyl, 4,5-dihydrothiazolyl, pyridinyl, oxazolyl,isoxazolyl, imidazolyl, pyrimidyl and tetrazolyl all optionallysubstituted with alkyl of 1 to 4 carbon atoms and phenyl optionallysubstituted with at least one member of the group consisting of --OH,alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen,--CF₃ and --NO₂.
 21. A method of claim 19 wherein R₃ is selected fromthe group consisting of hydrogen, alkyl of 1 to 4 carbon atoms and thesame halogen as R₅ and R₄ is selected from the group consisting ofhydrogen and the same halogen as R₅.
 22. A method of claim 19 wherein Xis --CF₃.
 23. A method of claim 19 wherein R₁ is hydrogen.
 24. A methodof claim 10 wherein R₅ is chlorine and R₃ and R₄ are individuallyselected from the group consisting of hydrogen and chlorine.
 25. Amethod of claim 19 wherein ##STR25## is --CHCl₂.
 26. A method of claim19 wherein R₂ is thiazolyl.
 27. A method of claim 19 wherein thecompound is2-dichloromethyl-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline-carboxamideand its salts with non-toxic, pharmaceutically acceptable acids andbases.